1. Field of the Invention
The present invention relates to a process for 5-aroylation of 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic esters or nitriles. The aroylated esters or nitriles are then optionally converted to the corresponding acids which are useful as antiinflammatory agents.
2. Prior Art
U.S. Pat. Nos. 4,087,539, 4,097,579, and 4,140,698, and U.S. applications Ser. Nos. 71,443, now U.S. Pat. No. 4,232,038, 71,444, now abandoned, and 157,719; disclose a method for 5-aroylation of 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic esters of nitriles to form first the corresponding 5-aroyl ester or nitrile, and then subsequent hydrolysis of that ester or nitrile to form the correponding free carboxylic acids. In the method therein described, the aroyl moiety is supplied in the form of the dimethylamide, and the reaction is carried out in the presence of an inorganic acid halide and an inert solvent. The resulting intermediate complex is then hydrolyzed by base to the 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic ester or nitrile; then stronger base or more vigorous conditions, followed by acidification, converts the ester or nitrile to acid. These previously disclosed processes have been unsatisfactory due to low yields and poor scalabilty.
Other methods of aroylation of the pyrrole nucleus, when not a part of the pyrrolopyrrole bicyclo system include reaction with an aroyl halide (U.S. Pat. No. 3,998,844) and with a 2-aryldithiolanium cation (U.S. Pat. No. 4,119,639). However, these methods suffer from the disadvantages of non-specificity as to the position aroylated and/or undue complexity and cost of reagent. In a manner more analogous to the previously described aroylation of pyrrolopyrroles using the aroyl dimethylamide, isolated pyrrole nuclei can be reasonably specifically aroylated using the corresponding aroyl morpholides, according to the description of White, J. and McGillivray, G.; J. Org. Chem. 42: 4248 (1977). Although these authors found that the morpholides were, in general, better reagents than the corresponding dimethylamides, they also found that alkyl (methyl) substitution at the ring nitrogen decreases the rate of reaction by a factor of 100 relative to the unsubstituted pyrrole when the morpholide is used. They attribute this decrease to steric factors related to the transition state. It is therefore implied that use of the morpholide would be disadvantageous for N-substituted pyrroles.
It is, therefore, quite surprising that substitution of the morpholide for the dimethylamide in the aroylation of the pyrrolopyrrole (which is, of course, substituted at the N-position of the pyrrole ring) enhances the rate of aroylation by a factor of approximately ten over the dimethylamide. The increase in rate is significant for reasons other than mere convenience because yields are enhanced in this process when reaction time is reduced. In addition, the morpholide reagent is intrinsically easier to handle than the dimethylamide.